Composition and method for relieving spasticity



Laboratories, Incorporated, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application July 30, 1956'.

Serial N0. 600,703

11 Claims. c1. 167-65) CDMPOSITION The present invention relates to novel medical preparations for the relief of spasticity and to a method for relieving spasticity. The present application is a continuation-in-part of application Serial No. 527,145, filed August 8, 1955, and now abandoned.

Spasticity is an uncontrolled, involuntary,'excessive contraction of one or more skeletal muscles and is a major component of many common disease conditions. Ithas been difficult if not impossible to relieve clinically. The manifestations of spasticity range in severity from those observed in minor transient injuries to localized areas, such as sprains and strains, through more serious conditions, such as chronic low back pain (lumbago), rheumatoid arthritis and rheumatoid spondylitis to the very severe incapacitating neurological diseases, such as multiple sclerosis, Parkinsons disease, cerebral palsy, and the like.

Mephenesin is known to relieve, in animals, experimentally induced spasticity, that is, to produce relaxation of the skeletal muscles, by a mechanism involving the depression of the polysynaptic pathways of the central nervous system. The activity of this compound is so low Sta-fates Patent and the duration so brief, that it is not feasible to employ this material clinically for the relief of spasticity. In addition, as is known, the administration of this material produces undesirable side effects, such as initial excitement, salivation, nausea and vomiting. There are also certain other compounds, discussed in the literature, which are stated to possess this ability to relax skeletal muscles. These compounds include Z-aminobenZoxazole, 2-amino-5-chlorobenzothiazole and 2-amino-6-methylbenzothiazole. However, these compounds also produce the undesirable effects mentioned above even at the dose levels insufficient to produce muscular relaxation (L. S. Goodman and A. Gilman, pp. 206408, The Pharmacological Basis of Therapeutics, second ed., 1955, The MacMillan Co., New York).

It is the principal object of the present invention to provide novel compositions possessing valuable therapeutic properties, that is, the ability to produce relaxation of the skeletal muscles by a mechanism involving the depression of the polysynaptic pathways of the central nervous system and thus the ability to relieve spasticity in animals and man.

It is another object of the invention to provide novel medical preparations which possess the beneficial action on the central nervous system referred to above, without, however, deleterious side effects, such as initial excitement, salivation, nausea or vomiting.

Still another object of the present invention is to provide novel medical preparations capable of producing, at reasonable doses, useful relaxation of skeletal muscles for substantial periods of time and which possess a wide margin between the effective dose and the lethal dose.

A further object is to provide a novel method for relieving spasticity in animals and man.

Other objects, including the provision of means for preparing the novel compositions, will become apparent Patented July 21, 1959 a from a consideration of the following specification and claims.

The composition of the present invention comprises a benzoxazole compound selected from the group consisting of 2-hydroxy benzoxazoles having the structural formula:

0 6 OH l l where X is selected from the group consisting of S-chloro, S-bromo, 6-chloro and 6-bromo, and salts thereof, and a pharmaceutical carrier.

The compositions of the present invention have been found to produce relaxation of the skeletal muscles by a therapeutic doses), have a wide safety margin between eifective dose and lethal dose, and lack any significant. side effects, including initial excitement, nausea or" vomiting. The compositions may therefore be readily' employed for the relief of spasticity in animals and man. Of special importance is the factthat the compositions.

are highly effective orally, and the preferred composi tions are, therefore, adapted for oral administration suchv as in the form of suspension, capsule or tablet dosageform. As will appear hereinafter,- numerous tests have: been made using compositions of the invention in various: species of animals and in man from which it is evident; that the compositions are highly effective in the relaxa-- tion of the skeletal muscles and are safe.

The 2-hydroxy-5- or 6-chloroor bromo-benzoxazole may be prepared by hydrolysis of the corresponding -amino-5- or 6-chloroor bromo-benzoxazole. Specific examples of the preparation of Z-hydroxy-S-chlorobenzoxazole and 2-hydroxy-6-bromobenzoxazole in accordance with this procedure are as follows:

EXAMPLE A A solution of 16.9 g. (0.1 mole) of 2-amino-5-chlorobenzoxazole in 200 ml. of 1 N HCl is refluxed until precipitation is complete. The resulting solid is collected by filtration, dissolved in 200 ml. of l N NaOH and the solution extracted with 50 ml. of ether. Acidification of the alkaline solution gives a precipitate which is purified by crystallization from acetone to give Z-hydroxy-S- chlorobenzoxazole melting at 191-1915 C.

The calculated N content for C7H4C1NO2 is 8.26; that found is 8.1.

EXAMPLE B A specific example of this procedure is as follows:

EXAMPLE C 9.8 g. 0.05 mole) of N-(5-chloro-2-hydroxyphenyl) urea, 4.1 ml. (0.05 mole) of concentrated HCl and 50 or bromo-phenylurea or 2-hyor bromo-phenylthiourea in acid EXAMPLE D A suspension of 14.6 g. (0.078 mole) of Z-amino- 4-bromophenoland 15.6 g. of sodiurnaoetate in 100 ml. o et iacta e. at d wit S r in with. a. oluti n of 9.4'g. (0.098 mole) of'phosgene in 200 ml. of ethyl acetate. After the addition is complete the mixture is re l fl ed for onehour andis then treated with 200 ml. of water. The'o rganic'layer is'separated, washed with water the solvent is removed in vacuo. The residue isdissolved in dilute sodium hydroxide and the solution treated with charcoal. The product. is precipitated with cone. hydrochloric acid and is recrystallized from aqueous methyl alcohol. There is obtained Z-hydroxy-S- bromobenzoxazole (5 bromobenboxazolinone), M.P. 214-216". 1

An example of the preparation of 2-hydroxy-6-chlorobenioxazole by chlorination of Z-hydroxybenzoxarole is asfollo'ws; Y

' EXAM LE. A, solution of. g. (0.07 mole) of benzoxazolinone in 200 ml. of chloroform is treated with 5.3 g. (0.07 mole) of chlorine. The, reaction mixture is stirred and cooled in an ice bath during the addition and stirring is con: tinued for one hour after the addition is complete. The

white precipitate is recrystallized from aqueous methyl alcohol. There is obtained 2-hydroxy-6 chlorobenzoxe azole (6 -chlorobenzoxazolinone), M.P. 196-196.

The described Z-hydroxybenzoxazoles possess acidic properties enabling them to. form salts with bases, and these compounds may .be employedas the acid or as a salt. These salts canreadily be prepared by reaction between the Z-hydroxybenzoxazole anda base, such as the alkali metal or alkaline earth metal oxides, hydroxides, carbonate, and the like; ammonia or a substituted ammonia, such as piperidine, butylamine, triethylamine,

ethanolamine, ethylenediamine, and the like.

If a salt is employed, the salt will be pharmaceutically acceptable and any toxicity or other undesirable effects which may be imparted should be taken into consideration as well known in the art. Pharmaceutically useful salts should not be substantially more toxic than the compound itself and should be able to be incorporated in liquid or solid pharmaceutical media for the preparation of therapeutically useful compositions.

In preparing the compositions of the present invention the benzoxazole compound will be combined with a significant amount of a pharmaceutical carrier. The carrier may take a wide varietyof forms depending upon the form of the preparation desired for administration. For parenteral injection the carrier may be sterile water with suitable adjustment of the pl-l toinsure solution of the ben zoxazole compound. For example, the compounds not salt form are practically insoluble in water while the salts vary in solubility, a nd insome cases the solubility of a salt is not sufiicient to provide the desired concentration. In this case the pH may be further adjust ed." As stated; the preferred form of administration of the present composition is oral, and the oral dosage maybe in the form of a suspension, powder adapted for suspension in liquid media, tablet or capsule. In preparing the compositions oral dosage form any of the usual pharmaceutical carrier media may be employed, such as gelatin, in the, case of capsules; sterile water,

pensions; starches, sugars, kaolin, salts, lubricants, binders, and the like in the case of powders and tablets. Tablets represent the most advantageous oral dosage form.

The amount of the composition administered and the amount of Z-hydroxybenzoxaxole. compound in the composition may vary somewhat depending upon the severity of the spasticity and upon the species being treated. As far as administration is concerned, the amount of composition administered may'range from that providing as little as about 2 milligrams of thebenzoxazole compound per kilogram of body weight to that providing as high as about milligrams per kilogram, preferably in the case of humans, that providingbetween about 5 and about 40 milligrams of bengoxazole compound per kilogram of body weight. In the composition, the concentration of the benzoxazole compound should be at least about 1%, by weight, preferably at leastahout 2%. h concentration of ssbsn p z e com un ma vary widely above these figures depending upon the form domestic animals,'like horses, theamount per dosage unit'may reach as high as about-10,000 milligrams. In the case of compositions adapted for human administra tion, the amount will generally range between about 100 and about 1000 milligrams of benzoxazole compound'per dosage unit.

The present invention will be more readily appreciated from a consideration of the following specific examples which are given for the purpose of illustration and arev not intended to limit the scope of the invention in any way. In these examples, as is customary in pharmacologicalinvestigations, albino mice of a uniform age and weight and from a standard strain are used as a primary test object since they are readily available andsincethe relative activity of depressant drugs in these animals as compared-to useful actions in man is well known. Results have also been confirmedby repetition in higher animal species includingrats, hamsters, dogs, cats and guinea pigs and some of this is-referred to in examples below. 'Finally, results have been confirmed in man. The primary criterion used for the presence of skeletal muscular relaxation in animals, especially the smaller animals, is the inability of the animal to roll over when placed flat upon its back. This is a convenient end point for the experimental observer, but is far in excess of the amount of skeletal muscular relaxation desired in man. Much of the following data are based on this observa; tion although numerous concurrent confirmatory observations of skeletal muscular relaxation were made. Be: cause of the foregoing and because of expected differences in the relative responsiveness of man and animal to drugs of this type, much of the following data are basedon doses that produoe efiects that could be considered excessive for ordinary clinical use.

EXAMPLES 1-11 In these examples is used a 2% suspension of 2-hydroxy-S-chlorobenzoxazole in an aqueous solution con- EXAMPLES III-VII 6 EXAMPLE XV Oral preparations of 2-hydroxy-S-chlorobenzoxazole are given to 7 dogs in dosages ranging from 200 to 265 mg./kg. of body weight, and the following typical results In these examples, five groups (designated groups III through VII of 2-7 albino mice receiver intraperitoneal are Obtained: injections of a 1% solution of Z-hydroxy-S-chlorobenz- Galas/U168 cofltalflmg' Z-hYdTOJfY'5-Ch10f0b611Z0XaZ01e oxazole in water containing suflicient sodium hydroxide lfnbedded 111 f IIVBI are glvell Q g to provide a pH of 11. In all cases within a few minutes Welghlng 111 all a i to P Y F 220 f of loss of righting reflex occurs and the'duration of this 10 drug P kllograni of y g With n 7 0 minutes eflect is noted and set forth in Table A. The doses, in P i shows sllght ataXla and 11100 fdlnat1011- Thls terms of mg of the benzoxazole per kil f body nitial sign of skeletal muscular relaxation increases in weight, are also set f thi 1 intensity until the animal can no longer stand at 110 T bl A rrnnutes. The intensity of this effect is strictly equiva-, a e lent to the loss of righting reflex described above for the smaller animals. However, it continues to increase until Group g ai g g g g g the animal is no longer able to swallow or to move its ingroup min) tongue although respiration appears normal or only slightly depressed at 110 minutes. After this maximal 2 75 4.5 eflect is reached it is maintained for an indefinite period, 3 but slowly diminishes in intensity until the animal is able 7 200 04 to walk 108 minutes later. Seventy-one minutes after this 5 225 89 time the animal appears and acts approximately normal.

1 This figure is for the three mice that survive. In the other two EXAMPLES XVI-XXXV respiratory failure occurs in 10 minutes. 2

EXAMPLES VHLX The following table illustrates, without undue repetition of the foregoing examples, the comparable skeletal muscle In these examples, three groups (designated groups relaxant properties of 2-hydroxy-6-chlorobenzoxazole, 2- VIII through X) of two albino rats are given oral adhydroxy-S-brornobenzoxazole and 2-hydroxy-6-bromoministrations of a 2% solution of 2-hydroxy-5-chlorobenzoxazole:

TableB Albino mice. P0, Albino mice, IP, Hamsters, P0, X LDsu/PD LDm/PD LD /PD Rats, P0, LRR Rabbits, IV, LRR

and LRR and LRR and LRR 5-01 640/300, LRR138 at333 200/95, LRR: 41' at 800/510, LRR: 44' at LRR: 240+ at LRR: 7' at 30 mg./

mg./kg. (XVI). 135g trig/kg. mg./kg. (XIX). kg. (XX). 6-C1 2,180/940, LRR: 240' at 350/180, LlRRz47at 900 500, LRR; 107' at LRR: as at 1,000 LRR: 4' at 50 mg./

940 mgJkg. (XXI). %80 13%.)lkg. mg./kg. (XXIV). kg. (XXV). 5-Br 1, 440/940, LRR:120 at 280/120, L'RR: 28' at 900 300, LItR: 70' at LRR: 04' at 1,000 LEE: 4' at 50 mg.

940 mgJkg. (XXVI). 180 rug/kg. 300 mgJkg. mg./kg. (XXIX). kg. (XXX).

(XXVII). (XXVIII). 6-Br 2,000 1000, LRR: 02' at 350/280, LRRz8 at 1,000/700,LRR: 210' at LRR: 1,440+ at- LEE: 4' at 50 mg./

1,000 mgJkg. 280 tug/kg. 800 lug/kg. 1,000 mgJkg. kg. (XXXV). (XXXI). (XXXII). (XXXIII). (XXXIV).

benzoxazole in water containing suflicient sodium hydroxide to provide a pH of 11.

Group VIII receives 400 mg. of the benzoxazole per kilogram of body Weight. One rat loses the righting reflex in 20 minutes for a period of 44 minutes. The other doesnt fully lose the righting reflex.

Group IX receives 600 mg./kg. In 4 minutes, the righting reflex is lost for 110 minutes.

Group X receives 800 mg./kg. In 3 minutes loss of the righting reflex occurs and this progresses to respiratory failure in 30 minutes.

EXAMPLES XI-XIV In these examples four groups (designated groups XI through XIV) of two hamsters receive oral administrations of the solution employed in Examples VIII-X.

Group XI receives 300 mg. of the benzoxazole per kilogram of body weight, and loses the righting reflex in two minutes for a period of 4 minutes. Group XII receives 400 mg./kg. The righting reflex is lost in 3 minutes for a period of 29 minutes.

Group XIII receives 500 mg./kg. The righting reflex in this group is also lost in 3 minutes for a period of 29 minutes.

Group XIV receives 600 mg./kg. One animal loses its righting reflex in 2 minutes for 83 minutes. Respiratory collapse occurs in the other after 4 minutes.

In the above table PO means per os, or oral administration; IP means intraperitoneal administration; IV means intravenous administration; LD means the dose of compound, in milligrams per kilogram of body weight, to be lethal to half of a group of ten species tested; PD means the dose of compound, in milligrams per kilogram of body weight, to produce loss of righting reflex, or flaccid paralysis, in half of a group of ten species tested, and LRR means the average duration of loss of righting reflex for those losing their righting reflex at the dose indicated and is given in minutes at an indicated dose in milligrams of compound per kilogram of body weight.

In the examples set forth in the first and third columns of Table B, the compounds were in the form of a 2%, by weight, suspension in an aqueous solution consisting of 8.6% polyethylene glycol 300, 0.5% sodium carboxy methylcellulose and the remainder water. In the examples set forth in the second, fourth and fifth columns, the compounds were in the form of a 2%, by Weight, solution in water to which is added the minimal necessary amount of 10% sodium hydroxide solution to disslove the compound.

The following examples illustrate the preparation of typical compositions of the present invention in oral dosage unit form.

7 PLE 'mVI" Tlze following 'foirnula is for preparing 8000 tablets (10 grains) each containing 150mg. "of the '2-hydroxybenzoxazole compound:

In placeof the milk" sugar, dibasic calciumphosphate and the portion of. thejstarch making up the 'filler,there may be used sucrose, polyethylene glycol 4000, 'mannitol and/or calcium'carbonate in various combinations and proportions. Starch paste, acacia solution, glucose' solution, carboxymethylcellulose solution, shellac, 'or the like may be used in place of gelatin solution as. granulating agent. Calcium stearate is employedas lubricatingagent and may be replaced by magnesium stearate, stearic'acid,

talc or the like.

EXAMPLE XXXVII The following formula may be employed for preparing 10,000 tablets (11.25 grains) each containing 500 mg. of the 2-hydroxybenzoxazole compound:

2-hydroxybenzoxazole compound- 11'lbs., 162' grains.

Milk sugar 1 1b., 13 oz., 96'gr. Starch (filler) 1 1b., 13 oz., 96 gr. Polyethylene glycol 4000 7 oz., 24 gr.

Starch (disintegrating agent) 13 oz., 340 gr. Calcium stearate 1 oz., 180 gr.

Gelatin solution 1.5 pounds per gallon.

EXAMPLE XXXVIII The following formula maybe employedito' make 1000 #3 capsules each containing 100 mg. of the 2-hydroxybenzoxa'zole compound:

Z-hydroxybenzoxazole compound g 100 Milk sugar a g 150 Fill weight mg 250 In place of or in additionto the milk sugar may be used 'sucros, dicalcium phosphate, calcium carbonate, kaolin, mannitol and/r starch, and the like.

EXAMPLE XXXIX The following formula may be employed for preparing a suspension containing 250mg. of the '2-hydroxybenzoxazole compound 'per cc:

In place of the propylene glycol maybe used. polyethylene glycol and/orglycerine. The carboxymethyl cellulose may be replaced by any one of the natural gums used as suspending agents. The parahydroxybenzoic acid esters may be-replaced by any commonly used bacteriostatic agent, and other commonly used surface agents may be used in place of the polyoxyethylene sorbitan monooleate.

8 EXAMPLE XL The following formula illustrates the preparation of a suspension containing500 mgiper S'cc. of the 2-hydroxybenzoxazole compound:

Z-hydroxybenzbxazole compound g Carboxymethyl cellulose (low viscosity, type 70) g 20 70% sorbitol solution g.. 250 Granulated sugar g 375 Propylene glycol g '50 Methyl ester of parahydroxybenzoic acid g 1.5 Propyl ester of parahydroxybenzoic acid g 0.3 Polyoxyethylene sorbitan -monooleate g 0.5 Methyl salicylate -a cc -25 Water, Lq.s.ad.. a cc.. 1000 Compositions of the invention have been administered,

by'the' present time, to' many patients. The periods of administration have been as long as three months, and doses as large as 2 grams of 2-hydroxybenzoxazole compound a day have been used. Most patients received 250 mg. or more three or four times a day. The administration of these compositions has been found to produce a significant degree of relief from muscle stiffness, spasm and pain in patients with the fibrositic type of arthritic involvement and in rheumatoid spondylitis. 'The compositions also'..produce prompt symptomatic relief of a moderate to a marked degree from low back pain and muscle spasm, andlhave been shown 'toyproduce a substantial relief of excessive muscle tone in children with spasticity associated with cerebral palsy.

Modification is possible in the selection of carrier material and'in the amount'thereof in preparing compositions in accordance with the present invention without "departing from the scope thereof.

I claim:

1. pharmaceutical composition comprising at least about 1%, by weight, of a Z-hydroxybenzoxazole com- ;pound selected from the group consisting of 2-hydroxybenzoxazoles having the structural formula:

where X is selected from'the group consisting of S-chloro, S-brdmo, 6-chlor0 and 6-bromo, and salts thereof,'-and a liquid"ph'armaceutical carrier therefor suitablefor internal administration.

5. The product of claim 4 wherein said 2-hydroxybenzoxazole is suspended in said liquid pharmaceutical carrier.

' 6. 'A' pharmaceutical composition comprising at-least pound selected from the group of Z-hydroxybenzoxazoles having the structural formula:

Where X is selected from the group consisting of -chloro, 5-b1'omo, 6-chloro and 6-bromo, and salts thereof, and a solid pharmaceutical carrier therefor suitable for internal administration.

7. The product of claim 6 in tablet form.

8. The product of claim 7 wherein X is S-chloro.

9. A pharmaceutical composition in dosage unit form comprising, per dosage unit, at least about 25 milligrams of a 2-hydroxybenzoxazole compound selected from the group consisting of 2-hydroxybenzoxazoles having the structural formula:

where X is selected from the group consisting of S-chloro, S-bromo, 6-chloro and 6-bromo, and salts thereof, and a pharmaceutical carrier therefor suitable for internal administration.

10. The product of claim 9 containing between about and about 1000 milligrams of the Z-hydroxybenzoxazole compound per dosage unit.

11. The product of claim 9 wherein X is 5-ch1oro, and wherein the product contains between about 100 and about 1000 milligrams of Z-hydroxy-S-chlorobenzoxazole per dosage unit.

References Cited in the file of this patent UNITED STATES PATENTS Herdieckerhofi et al Feb. 15, 1938 Sam Feb. 5, 1957 OTHER REFERENCES 

1. A PHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ABOUT 1%, BY WEIGHT, OF A 2-HYDROXYBENZOXAZOLE COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-HYDROXYBENZOXAZOLES HAVING THE STRUCTURAL FORMULA: 